Itraconazole Inhibits the Growth of Cutaneous Squamous Cell Carcinoma by Targeting HMGCS1/ACSL4 Axis.

Background: Cutaneous squamous cell carcinoma (cSCC) is a common cutaneous cancer with increasing incidence. Itraconazole has been identified as a potential anticancer drug candidate. However, the role of itraconazole in cSCC was still unclear. Our objective is exploring the therapeutic potential of itraconazole in cSCC and investigate its molecular mechanism. Methods: The anti-proliferation effect of itraconazole was tested with CCK-8 assay and clone formation assay. Cell cycle distribution and apoptosis rate were detected using flow cytometry and TUNEL assay, respectively. Transcriptomic and proteomic analyses were used to explore the underlying anti-cancer mechanism. Luciferase reporter assay was used for promoter activity. Reactive oxygen species (ROS), lipid peroxidation and iron accumulation were examined. The in vivo efficacy of itraconazole was assessed in a xenograft model. Results: Itraconazole inhibited the cell proliferation, induced apoptosis and blocked cell cycle of cSCC cells. An integrated analysis of transcriptomic and proteomic analyses identified that 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) and acyl-CoA synthetase long-chain family member 4 (ACSL4) were significantly upregulated in A431 cells treated with itraconazole. HMGCS1 silencing reversed the antiproliferative activity of itraconazole in A431 cells. Dual-luciferase assay showed that itraconazole could promote HMGCS1 transcription. HMGCS1 silencing abated the expression of ACSL4 in A431 cells. The level of ROS, lipid peroxidation, as well as iron accumulation were increased by itraconazole. Moreover, treatment with itraconazole impeded tumor growth in A431-bearing mice. Conclusion: We proved itraconazole inhibits the growth of cSCC by regulating HMGCS1/ACSL4 axis.

Prenylated coumarins from the fruits of Artocarpus heterophyllus with their potential anti-inflammatory and anti-HIV activities.

A phytochemical investigation on the fruits of Artocarpus heterophyllus led to the isolation and characterisation of a new prenylated coumarin, artoheteronin (1), together with six known analogues (2-7). The chemical structure of 1 was elucidated using extensive spectral methods and the known compounds (2-7) were identified by comparing their spectral data with those reported in the literature. All known compounds (2-7) were isolated from the genus Artocarpus for the first time. The anti-inflammatory and anti-HIV activities of all isolated prenylated coumarins (1-7) were assessed in vitro. As a result, compounds 1-7 displayed notable inhibitory effects against nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro with the IC50 values in range of 0.58 ± 0.06 to 6.29 ± 0.12 µM. Meanwhile, compounds 1-7 exhibited notable anti-HIV-1 reverse transcriptase (RT) activities possessing EC50 values in the range of 0.18 to 9.12 µM.

Oroxylin A reverses hypoxia-induced cisplatin resistance through inhibiting HIF-1α mediated XPC transcription.

Hypoxia is a key concern during the treatment of non-small cell lung cancer (NSCLC), and hypoxia-inducible factor 1 alpha (HIF-1α) has been associated with increased tumor resistance to therapeutic modalities such as cisplatin. Compensatory activation of nucleotide excision repair (NER) pathway is the major mechanism that accounts for cisplatin resistance. In the present study, we suggest a novel strategy to improve the treatment of NSCLC and overcome the hypoxia-induced cisplatin resistance by cotreatment with Oroxylin A, one of the main bioactive flavonoids of Scutellariae radix. Based on the preliminary screening, we found that xeroderma pigmentosum group C (XPC), an important DNA damage recognition protein involved in NER, dramatically increased in hypoxic condition and contributed to hypoxia-induced cisplatin resistance. Further data suggested that Oroxylin A significantly reversed the hypoxia-induced cisplatin resistance through directly binding to HIF-1α bHLH-PAS domain and blocking its binding to HRE3 transcription factor binding sites on XPC promoter which is important to hypoxia-induced XPC transcription. Taken together, our findings not only demonstrate a crucial role of XPC dependent NER in hypoxia-induced cisplatin resistance, but also suggest a previously unrecognized tumor suppressive mechanism of Oroxylin A in NSCLC which through sensitization of cisplatin-mediated growth inhibition and apoptosis under hypoxia.